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Heme scavenging reduces pulmonary endoplasmic reticulum stress, fibrosis, and emphysema
Saurabh Aggarwal, … , Mark T. Dransfield, Sadis Matalon
Saurabh Aggarwal, … , Mark T. Dransfield, Sadis Matalon
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e120694. https://doi.org/10.1172/jci.insight.120694.
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Research Article Pulmonology

Heme scavenging reduces pulmonary endoplasmic reticulum stress, fibrosis, and emphysema

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Abstract

Pulmonary fibrosis and emphysema are irreversible chronic events after inhalation injury. However, the mechanism(s) involved in their development remain poorly understood. Higher levels of plasma and lung heme have been recorded in acute lung injury associated with several insults. Here, we provide the molecular basis for heme-induced chronic lung injury. We found elevated plasma heme in chronic obstructive pulmonary disease (COPD) (GOLD stage 4) patients and also in a ferret model of COPD secondary to chronic cigarette smoke inhalation. Next, we developed a rodent model of chronic lung injury, where we exposed C57BL/6 mice to the halogen gas, bromine (Br2) (400 ppm, 30 minutes), and returned them to room air resulting in combined airway fibrosis and emphysematous phenotype, as indicated by high collagen deposition in the peribronchial spaces, increased lung hydroxyproline concentrations, and alveolar septal damage. These mice also had elevated pulmonary endoplasmic reticulum (ER) stress as seen in COPD patients; the pharmacological or genetic diminution of ER stress in mice attenuated Br2-induced lung changes. Finally, treating mice with the heme-scavenging protein, hemopexin, reduced plasma heme, ER stress, airway fibrosis, and emphysema. This is the first study to our knowledge to report elevated heme in COPD patients and establishes heme scavenging as a potential therapy after inhalation injury.

Authors

Saurabh Aggarwal, Israr Ahmad, Adam Lam, Matthew A. Carlisle, Changzhao Li, J. Michael Wells, S. Vamsee Raju, Mohammad Athar, Steven M. Rowe, Mark T. Dransfield, Sadis Matalon

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Figure 1

Plasma heme and ER stress levels are elevated in patients with very severe COPD and in ferrets exposed to cigarette smoke.

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Plasma heme and ER stress levels are elevated in patients with very seve...
Total heme levels were measured in the plasma of COPD patients and their healthy counterparts. Although total heme levels were not significantly higher in COPD patients compared with the healthy individuals (P = 0.06) (n = 18–22) (A), the stratification of patients according to the severity of the disease revealed significantly elevated plasma heme in COPD patients with GOLD stage 4 disease compared with the healthy individuals or patients with the mild disease (n = 6–18) (B). Plasma heme levels were also significantly higher in ferrets exposed to cigarette smoke for 6 months, which induced emphysema and attenuated lung function (n = 6–8) (C). ELISA showed that GOLD stage 4 COPD patients had significantly higher levels of ER stress marker Grp78/Bip (n = 6–14) (D). Values are means ± SEM. *P < 0.05 versus healthy patients or air-exposed ferrets; †P < 0.05 versus COPD GOLD stage 2; ‡P < 0.05 versus COPD GOLD stage 3, by unpaired t test for 2 groups or 1-way ANOVA followed by Tukey’s post hoc testing for more than 2 groups.

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